Estradiol administration initiates rapid and dramatic growth responses in the uterus. This growth requires the coordinated control and sequential increase in expression of many genes. Although it has been shown that estradiol increases very early proto-oncogene expression in the ovariectomized rat uterus, the relationship of these inductions to uterine mitogenic responses in specific uterine tissues has not been determined. We propose that estrogens elicit their effects in causing uterine cell proliferation through the increased expression of proto-oncogenes. To elucidate the role of oncogene expression in steroid-induced uterine responses, the following specific aims are proposed to examine the kinetics of induction, the tissue location, and hormonal control of uterine proto-oncogene expression. (1) Uterine mRNA's encoding c-jun, jun B, jun D, c-fos, c-ski and c-myc will be quantitated at short intervals after estradiol treatment of ovariectomized mature rats. With the kinetics of the inductions established, the hormone specificity and dose responses of the inductions will be determined. (2) In situ hybridization and immunohistochemistry will be used to identify the specific uterine cell types expressing each proto-oncogene. (3) To determine whether altered proto-oncogene expression is a primary response to estradiol, the sensitivity of increases in mRNA levels of cycloheximide and actinomycin D will be determined. (4) The mechanisms by which estradiol increase proto- oncogene expression will be examined by determining the effects of the hormone on rates of transcription and on levels of mRNA translational activity. (5) Treatments with short acting estrogens which initiate only early uterine responses will be used to examine the functions of proto-oncogene expression in early components of the response to estradiol. Treatment with progesterone which redirects the tissue location of uterine responses estradiol will be used to examine the tissue specificity of proto-oncogene expression. The information gained from these proposed studies will enable us to examine the biochemical function of oncogene products in the uterine response to estradiol. Improved understanding of these mechanisms will enhance our capability of controlling normal uterine physiology and cancer cell proliferation.
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